Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

FMR1 前突变母携带者的衰老症状轨迹

• 批准号: 10445687
• 负责人: Jessica Klusek
• 金额: $ 60.67万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445687
• 关键词: Activities of Daily Living; Adopted; Adult; Advocate; Affect; Age; Aging; Anxiety; Autoimmune; Autonomic Dysfunction; Autonomic nervous system; Biological; Biological Factors; Caring; Characteristics; Child; Child Rearing; Classification; Clinical; Clinical Management; Cross-Sectional Studies; DNA Sequence Alteration; Data; Development; Environmental Risk Factor; Executive Dysfunction; Eye; FMR1; FMR1 Premutation; FMRP; Family; Fragile X Syndrome; Functional disorder; Future; Gene Abnormality; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Glean; Goals; Growth; Heart Rate; High Prevalence; Impairment; Individual; Infertility; International; Investigation; Life; Long-Term Effects; Mental Depression; Mental Health; Messenger RNA; Modeling; Molecular Abnormality; Molecular Genetics; Mothers; Mutate; Neurodegenerative Disorders; Outcome; Parents; Partner in relationship; Phenotype; Physiological; Play; Premature Menopause; Prevention; Process; Public Health; Risk; Risk Factors; Role; Sinus Arrhythmia; Statistical Methods; Stress; Symptoms; Testing; Time; United States; Woman; Work; age related; aged; chronic painful condition; clinical risk; disability; disorder risk; executive function; experience; human old age (65+); improved; improved outcome; innovation; longitudinal design; men; middle age; premature; respiratory; social; social communication; social deficits; social skills; stressor

PROJECT SUMMARY/ABSTRACT About 1 in 151 women in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Mothers who carry the FXpm are at risk for passing the mutated gene to their children, which may result in fragile X syndrome. The FXpm is also associated with substantially increased risk for disease, including neurodegenerative disease, premature menopause, psychiatric involvement, and executive and social deficits. New evidence suggests that FXpm carrier mothers may experience premature age-related decline across multiple symptom domains. The aging expression of FXpm phenotype is particularly concerning when applied within the context of fragile X families because these symptoms impact not only the carrier mother, but also her ability to care and advocate for her children with fragile X syndrome. However, almost all evidence of age- related decline in this group has been gleaned from cross-sectional data that are insufficient for drawing robust longitudinal trajectories. This represents a substantial barrier to effective clinical management, as we lack the data needed to understand the long-term effects of the FXpm genotype and its implications for families. This proposal seeks to determine the stability of key FXpm phenotypes (mental health, executive, social) across midlife and early old age in FXpm carrier mothers compared to healthy controls (Aim 1); investigate autonomic and molecular-genetic factors associated with age-related symptom expression and their interface with parenting stress (Aim 2); and evaluate functional limitations associated with FXpm symptoms across age (Aim 3). We will accomplish these aims by adopting an accelerated longitudinal design to track age-related change occurring across 45-80 years in 75 FXpm carrier mothers compared to 75 control mothers. The over- arching goal is to inform the critical age periods and risk factors in age-related decline, as well as to lay the groundwork for future mechanistic studies. This work is necessary to develop strategies to ameliorate FXpm symptoms, which will improve outcomes for both FXpm carrier mothers and their children with fragile X syndrome.

项目摘要/摘要 在美国，大约151名妇女是遗传异常的携带者，称为FMR1 Premunt （FXPM）。携带FXPM的母亲有可能将突变基因传递给子女的风险，这可能会导致 在脆弱的X综合征中。 FXPM还与疾病的风险大大增加有关，包括 神经退行性疾病，更年期，精神科参与以及执行和社会缺陷。 新的证据表明，FXPM承运人母亲可能会经历与年龄相关的过早下降 多个症状领域。 FXPM表型的衰老表达在应用时特别关注 在脆弱的X家族的背景下，因为这些症状不仅会影响承运人的母亲，而且会影响她 能够照顾和倡导脆弱X综合征的孩子。但是，几乎所有年龄的证据 该组的相关下降是从横截面数据中收集的，这些数据不足以绘制鲁棒 纵向轨迹。这代表了有效临床管理的实质性障碍，因为我们缺乏 了解FXPM基因型的长期影响及其对家庭的影响所需的数据。 该建议旨在确定关键FXPM表型（心理健康，执行，社会）的稳定性 与健康对照组相比，FXPM载体母亲的中年和早年的年龄（AIM 1）；调查 与年龄相关症状表达相关的自主和分子遗传因素及其界面 育儿压力（AIM 2）；并评估与FXPM症状相关的功能限制 （目标3）。我们将通过采用加速纵向设计来跟踪与年龄相关的纵向设计来实现这些目标 在75个FXPM载体母亲中，与75名对照母亲相比，在45 - 80年中发生的变化发生在45 - 80年中。超过 拱门目标是告知与年龄相关的关键年龄时期和风险因素，并铺设 未来机械研究的基础。这项工作对于制定改善FXPM的策略是必要的 症状，这将改善FXPM携带者母亲及其子女脆弱X的预后 综合征。